Polyaromatic esters of macrolidic and lincosamidic antibiotics and pharmaceutical and cosmetic compositions containing them

ABSTRACT

Polyaromatic esters of macrolidic and lincosamidic antibiotics are employed in the treatment of acne.

The present invention relates to polyaromatic esters of macrolidic andlincosamidic antibiotics, to a process for their preparation and topharmaceutical and cosmetic compositions containing them for thetreatment of various dermatoses, and principally in the treatment ofacne.

More particularly, the esters in accordance with the present invention,are intended for the treatment of dermatoses, infectious or not.

In the treatment of acne, erythromycin among the macrolides as well asclindamycin among the lincosamides have been more particularlyrecommended, but their use requires (particularly for erythromycin)relatively high concentrations so as to obtain a satisfactory result.

Moreover, treatment with these antibiotics has proved, in certain cases,less effective, in the measure where certain strains ofpropionibacterium acnes have exhibited a progressive resistance in theirregard.

The topical application of clindamycin and more particularlyerythromycin collides, besides, with a problem of penetration throughthe corneum stratum limiting from this fact their efficacy.

The esters of antibiotics in accordance with the invention provide asatisfactory solution to the problem raised by the use of theseantibiotics in the treatment of acne, in the measure where it isestablished that these esters have an activity on propionibacteriumacnes, the main germ responsible for the inflammation phenomena of theskin.

The polyaromatic esters in accordance with the invention have from thefact of their structure a pronounced lipophilic character whichfacilitates a better penetration across the epidermis.

The new esters in accordance with the invention are well tolerated bythe skin and are revealed to be much less toxic when taken orally thanthe antibiotic/acid combination.

Besides, they exhibit, with respect to known esters, the advantage ofpossessing a potential comedolytic activity due to the correspondingacid chain, which confers to these esters an image of a "prodrug".

The state of the art relative to esters of macrolides is representedprincipally by French patent o. 85.07287 (2.582.000) which relates topoly unsaturated fatty esters of erythromycin A such as the linoleate,and the linolenate of erythromycin A.

The state of the art relative to esters of lincosamides is representedprincipally by German patent No. 2.017.003 which describes thepreparation of esters of lincomycin and clindamycin whose acyl chain hasbetween 1 and 18 carbon atoms.

The present invention relates to as a new industrial product,polyaromatic esters of macrolides or lincosamides, said esters havingthe following general formula: ##STR1## wherein R represents a macrolideor lincosamide radical,

n and m are 0 or 1 with the proviso that n and m are not simultaneouslyequal to 1,

A represents methylene or ethylene, unsubstituted or substituted with alower alkyl radical having 1-4 carbon atoms,

R₁, R₂, R₃ and R₄, each independently, represent hydrogen or alkylhaving 1-6 carbon atoms, or R₁ and R₃ taken together form a methylene orethylene radical when A represents ethylene,

R₇ represents hydrogen, hydroxy, alkoxy having 1-4 carbon atoms oracyloxy having 1-4 carbon atoms,

R₈ represents hydrogen or alkoxy having 1-4 carbon atoms, or

R₇ and R₈ taken together form an oxo (=O) radical or a methano (=CH₂)radical, and

R₅ and R₆ represent hydrogen or methyl or R₅ and R₆, taken together,form a vinylene (--CH=CH--) radical and

the isomers, mixtures and salts of said esters.

Representative lincosamides include lincomycin and clindamycin.

A - The esters of erythromycin A and roxithromycin can be represented bythe formula ##STR2## wherein R'₁ represents O (erythromycin A) orN˜O-CH₂ -O-CH₂ -CH₂ -O-CH₃ (roxithromycin), and

R' represents the following acyl radical: ##STR3## wherein A, R₁ to R₈,n and m have the same meanings given above.

B - The esters of oleandomycin can be represented by the followingformula: ##STR4## wherein R'₂ or R'₃ represents R' or hydrogen with theproviso that at least one of R'₂ and R'₃ represents R', and

R' has the same meaning given above.

These esters are those in position 2' and/or 4", but they can beprovided in the form of a mixture.

C - The esters of josamycin can be represented by the following formula:##STR5## wherein R'₂ and R'₃ represents R' or hydrogen with the provisothat at least one of R'₂ and R'₃ represents R' and

R' has the same meaning given above.

These esters are those in position 9 and/or 2', but they can be providedin the form of a mixture.

D - The esters of spiramycins can be represented by the followingformula: ##STR6## wherein R'₂ or R'₃ represents R' or hydrogen with theproviso that at least one of R'₂ and R'₃ represents R' and

R'has the same meaning given above and

R" represents hydrogen (spiramycin I), acetyl (spiramycin II) orpropionyl (spiramycin III).

These esters of spiramycin (I), (II) and (III) are those in position 2'and/or 4" and they can be provided in the form of a mixture.

E - The esters of lincomycin and clindamycin can be represented,respectively, by the following formulas (VI) and (VII): ##STR7## whereinR' has the same meaning given above.

The esters of lincomycin (VI) and clindamycin (VII) are preferably thosein position 3. However, they can be provided in the form of mixtureswith the esters in position 2, 4 and 7 of lincomycin and with esters inposition 2 and 4 of clindamycin.

Representative esters of formula I, in accordance with the invention,include the following:

2'O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]erythromycin A,

2'-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]roxithromycin,

3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]clindamycin,

9 and 2'-O-[6[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]josamycin,

2'-O-[6-[(5,6,7,8-tetrahydro-2-naphthyl)carbonyl]-2-naphthoyl]roxithromycin

2'-O-[6-[(1,1,3,3-tetramethyl-5-indanyl)carbonyl]-2-naphthoyl]oleandomycin,

9 and 2'-O-[6-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]-2-naphthoyl]josamycin,

2'-O-[6-[(1,1,2,3,3-pentamethyl-5-indanyl) hydroxymethyl]-2-naphthoyl]spiramycin (I), (II) and (III),

2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]erythromycin A,

3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]clindamycin and its isomer at position 4,

2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methyl]-2-naphthoyl]spiramycin(I). (II) and (III),

3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acetoxymethyl]-2-naphthoyl]lincomycin,

2'-O-[6-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-ethenyl]-2-naphthoyl]erythromycinA, and

3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) butoxymethyl]-2-naphthoyl]clindamycin.

The present invention also relates to a process for preparing thepolyaromatic esters of antibiotics of formula (I) according to thepresent invention.

Various procedures for esterification can be employed, but preferablythis esterification is carried out in an anhydrous organic solventmedium, preferably in tetrahydrofuran alone or in mixture with anotherorganic solvent such as pyridine, by reacting an excess of mixedanhydride of the formula: ##STR8## wherein A, R₁ to R₈, n and m have thesame meanings given above,

the said anhydride being prepared in situ, (for example starting withethyl chloroformate and the corresponding acid) with a macrolide orlincosamide in base form, in the presence of an organic or mineral basesuch as pyridine and/or sodium bicarbonate and/or triethylamine.

This method with mixed anhydride permits to obtain preferentially estersin position 2' of macrolides and/or in position 9 principally forjosamycin and/or in position 4" principally for the spiramycins and theesters in position 3 of lincosamides in good yield conditions.

The other procedures of esterification principally of lincomycin andclindamycin by the method using imidazolides of corresponding acids inan anhydrous solvent such as N,N-dimethylformamide in the presence of abase such as sodium or potassium tert. butylate lead to a mixture ofesters of these antibiotics.

The present invention also relates to pharmaceutical compositions thatcan be administered topically, orally, parenterally or rectally as wellas to cosmetic compositions for the treatment of various dermatoses,principally acne, these compositions being provided in anhydrous formand containing at least one ester in accordance with the invention, suchas defined above, in an amount ranging from 0.001 to 10 weight percent,but preferably from 0.01 to 1 weight percent, based on the total weightof the composition.

For the preparation of compositions, according to the invention,containing as the active component, at least one ester according to theinvention such as defined above, there can be employed vehicles andadjuvants described in the literature for pharmaceuticals, cosmetics andrelated fields.

For the preparation of solutions, there can be employed, for example, anacceptable organic solvent from a physiologic view point.

The acceptable organic solvent is selected principally from the groupconsisting of acetone, isopropyl alcohol, triglycerides of fatty acids,C₁ -C₄ alkyl esters of short chain acids, polytetrahydrofuran ethers andsilicones such as cyclomethicones.

The compositions according to the invention can also include athickening agent such as a cellulose derivative in an amount rangingfrom 0.5 to 20 weight percent based on the total weight of thecomposition.

The compositions according to the invention can also contain incombination with at least one ester according to the invention, at leastone other known anti-acne agent.

If necessary, a conventional adjuvant selected from the group consistingof antioxidants, preservatives, perfumes and dyes can be added

Representative useful antioxidants include, for instance, t-butylhydroxyquinone, butylhydroxy anisole, butylhydroxy toluene and α-tocopherol andits derivatives.

The pharmacologic and galenic transformations of the compounds of thepresent invention are effected in a known manner.

The galenic forms can be, for topical applications, creams, milks, gels,more or less thick lotions, lotion-impregnated pads, pomades, sticks oreven aerosol formulations provided in the form of sprays or foams.

The compositions for oral administration can be provided in the form oftablets, gelules, lozenges, syrups, suspensions, emulsions, powders,granules or solutions.

The compositions can also be provided in the form of suppositories.

The treatment of acne using the topical compositions of the inventioncomprises applying, two or three times each day, a sufficient amount onthe areas of the skin being treated and this for a period of timeranging from 6 to 30 weeks and preferably from 12 to 24 weeks.

The compositions according to the invention can also be used as apreventative, i.e. on the areas of the skin susceptible of beingattacked by acne.

There are now given, as an illustration, several examples of thepreparation of the polyaromatic esters of antibiotics in accordance withthe invention as well as several examples of pharmaceutical or cosmeticcompositions for the treatment of dermatoses, principally of acne.

EXAMPLE 1 Preparation of2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]erythromycinA

In a round bottom flask, under an inert atmosphere, there are dissolved6.4 g (16.6 mmoles) of6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthalenecarboxylic acid in 35 ml of anhydrous tetrahydrofuran; the reactionmixture is cooled to 0° C., and there are then added 2.3 ml (16.6mmoles) of triethylamine and 1.6 ml (16.6 mmoles) of ethylchloroformate. The solution is stirred for 5 minutes, and there areadded 20 ml of anhydrous pyridine, then 4.9 g (6.7 mmoles) oferythromycin A previously dissolved in 150 ml of tetrahydrofuran. Thereaction mixture is then stirred for 10 hours and the temperature ispermitted to return to ambient temperature (chromatography on thin layersilica gel: methylene chloride (90)/methanol (10)). The solution ispoured into 60 ml of water and extracted with ethyl acetate. The organicphase is dried on magnesium sulfate, filtered, and then concentratedunder a partial vacuum. The crude product thus obtained ischromatographed on a silica gel column (HPLC) by using as the eluant:ethyl acetate (7)/hexane (3) to result in the isolation of 4.2 g (57%yield) of 2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]erythromycin A.

M.P.=152° C. (hexane/ethyl acetate)

[α]_(D) ²² =-65° (C=2 mg/ml-dichloromethane).

Microanalysis: C₆₃ H₉₁ NO₁₅ ; M.W.=1102.4

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Calculated, %                                                                              68.04        8.32   1.27                                         Found, %     68.66        8.33   1.25                                         ______________________________________                                    

NMR ¹³ C (CDCl₃, internal ref. T.M.S.)

Negative γ effects in 1' (-2.2 ppm) and 3' (-1.5 ppm) indicate theposition of the ester at the 2' position.

EXAMPLE 2 Preparation of3-O-[6-[(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]clindamycin and its 4 position isomer

In a round bottom flask, under an inert atmosphere, there are dissolved1 g (2.6 mmoles) of6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) hydroxymethyl]-2-naphthalene carboxylic acid in 20 ml of anhydroustetrahydrofuran; the reaction mixture is cooled to 0° C., and there arethen added 0.36 ml of triethylamine and 0.25 ml (2.6 mmoles) of ethylchloroformate; the solution is stirred for 1 hour, and there are added0.35 ml of anhydrous pyridine, the then 370 mg (0.9 mmole) ofclindamycin previously dissolved in 15 ml of tetrahydrofuran. Thereaction mixture is then stirred for 10 hours and the temperature ispermitted to return to ambient temperature (chromatography on thin layersilica gel: methylene chloride 90%/methanol 10%.

The solution is poured into 25 ml of water and then extracted with ethylacetate. The organic phase is dried on magnesium sulfate, filtered, andthen concentrated under a partial vacuum. The crude product thusobtained is chromatographed on a silica gel column (HPLC) by using asthe eluant: ethyl acetate (7)/hexane (3) to result in the isolation of285 mg (45% yield) of3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]clindamycinand its 4 position isomer.

Microanalysis: C₄₄ H₅₉ N₂ O₃ SCl·3.5H₂ O; M.W.=794.5

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated, %      66.51  7.48                                                Found, %           66.75  7.97                                                ______________________________________                                    

NMR ¹³ C (CDCl₃, internal ref. T.M.S.) conforms to the expectedspectrum.

In accordance with the same operating procedures described above inExamples 1 and 2, the other esters listed above have been prepared.

PHARMACEUTICAL AND COSMETIC COMPOSITIONS

    ______________________________________                                        A. Gel for the topical treatment of acne                                      ______________________________________                                        Hydroxypropyl cellulose  1      g                                             Butylhydroxy toluene     0.05   g                                             2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8,                                                                  0.5    g                                             tetramethyl-2-naphthyl) carbonyl]-                                            2-naphthoyl] erythromycin A                                                   Isopropanol, sufficient amount for                                                                     100    g                                             Hydroxypropyl cellulose  1      g                                             Butylhydroxy toluene     0.05   g                                             3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-                                                                   0.5    g                                             tetramethyl-2-naphthyl)                                                       hydroxymethyl]-2-naphthoyl]                                                   clindamycin and its 4 position                                                isomer                                                                        Isopropanol, sufficient amount for                                                                     100    g                                             ______________________________________                                        B. Lotion for the topical treatment of acne                                   ______________________________________                                        Butylhydroxy toluene     0.05   g                                             2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-                                                                  1      g                                             tetramethyl-2-naphthyl) carbonyl]-                                            2-naphthoyl] erythromycin A                                                   Triglycerides of C.sub.8 -C.sub.12 fatty acids,                                                        100    g                                             sufficient amount for                                                         Butylhydroxy toluene     0.05   g                                             3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-                                                                   1      g                                             tetramethyl-2-naphthyl)                                                       hydroxymethyl]-2-naphthoyl]                                                   clindamycin and its 4 position                                                isomer                                                                        Triglycerides of C.sub.8 -C.sub.12 fatty acids,                                                        100    g                                             sufficient amount for                                                         ______________________________________                                        C. Stick for the topical treatment of acne                                    ______________________________________                                        White petrolatum         52     g                                             Petrolatum oil           15     g                                             Refined paraffin         32     g                                             2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-                                                                  1      g                                             tetramethyl-2-naphthyl) carbonyl]-                                            2-naphthoyl] erythromycin A                                                   White petrolatum         52     g                                             Petrolatum oil           15     g                                             Refined paraffin         32     g                                             3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-                                                                   1      g                                             tetramethyl-2-naphthyl)                                                       hydroxymethyl]-2-naphthoyl]                                                   clindamycin and its 4                                                         position isomer                                                               ______________________________________                                    

What is claimed is:
 1. A polyaromatic ester of a macrolide orlincosamide having the formula ##STR9## wherein R represents a macrolideselected from the group consisting of:erythromycin A substituted in the2' position, roxithromycin substituted in the 2' position, oleandomycinsubstituted in the 2' position, oleandomycin substituted in the 4"position, oleandomycin substituted in the 2' and 4" positions, josamycinsubstituted in the 9 position, josamycin substituted in the 2' position,josamycin substituted in the 9 and 2' positions, spiramycin (I)substituted in the 2' position, spiramycin (I) substituted in the 4"position, spiramycin (I) substituted in the 2' and 4" positions,spiramycin (II) substituted in the 2' position, spiramycin (II)substituted in the 4" position, spiramycin (II) substituted in the 2'and 4" positions, spiramycin (III) substituted in the 2' position,spiramycin (III) substituted in the 4" position, spiramycin (III)substituted in the 2' and 4" positions, or R represents a lincosamideselected from the group consisting of:lincomycin substituted in the 3position, clindamycin substituted in the 3 position, lincomycinsubstituted in the 2, 4 and 7 positions and clindamycin substituted inthe 2 and 4 positions, n and m are 0 or 1 with the proviso that n and mare not simultaneously equal to 1, A represents methylene or ethylene,unsubstituted or substituted by lower alkyl having 1-4 carbon atoms, R₁,R₂, R₃ and R₄, each independently, represent hydrogen or alkyl having1-6 carbon atoms, or R₁ and R₃ taken together from methylene or ethylenewhen A represents ethylene, R₇ represents hydrogen, hydroxy, alkoxyhaving 1-4 carbon atoms or acyloxy having 1-4 carbon atoms, R₈represents hydrogen or alkoxy having 1-4 carbon atoms, or R₇ and R₈taken together form an oxo or methano radical, and R₅ and R₆ representhydrogen or methyl, or R₅ and R₆, taken together, form a vinyleneradical, and the isomers, mixtures and salts of said esters.
 2. Theester of claim 1 selected from the group consistingof2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]erythromycin A,2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]roxithromycin,3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]clindamycin,9 and 2'-O-[6[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-2-naphthoyl]josamycin,2'-O-[6-[(5,6,7,8-tetrahydro-2-naphthyl)carbonyl]-2-naphthoyl]roxithromycin2'-O-[6-[(1,1,3,3-tetramethyl-5-indanyl)carbonyl]-2-naphthoyl]oleandomycin,9 and 2'-O-[6-[(1,1,2,3,3-pentamethyl-5-indanyl)carbonyl]-2-naphthoyl]josamycin,2'-O-[6-[(1,1,2,3,3-pentamethyl-5-indanyl) hydroxymethyl]-2-naphthoyl]spiramycin (I), (II) and (III),2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]erythromycin A,3-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)hydroxymethyl]-2-naphthoyl]clindamycin and its isomer at position 4,2'-O-[6-[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl)methyl]-2-naphthoyl]spiramycin(I). (II) and (III),3-O-[6-[(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acetoxymethyl]-2-naphthoyl]lincomycin,2'-O-[6-[(2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2ethenyl]-2-naphthoyl]erythromycinA, and 3-O-[6-[(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)butoxy methyl]-2-naphthoyl]clindamycin.
 3. A pharmaceutical or cosmeticcomposition for the treatment of dermatoses comprising in an anhydrousvehicle, as the active component, a pharmaceutically or cosmeticallyeffective amount of at least one ester of claim
 1. 4. The composition ofclaim 3 wherein said ester is present in an amount ranging from 0.001 to10 weight percent based on the total weight of said composition.
 5. Thecomposition of claim 3 wherein said ester is present in an amountranging from 0.01 to 1 weight percent based on the total weight of saidcomposition.
 6. The composition of claim 3 wherein said anhydrousvehicle is acetone, isopropyl alcohol, triglycerides of fatty acids, C₁-C₄ alkyl ester of a short chain acid, poly tetrahydrofuran ether, asilicone or a mixture thereof.
 7. The composition of claim 3 which alsocontains a thickening agent in an amount ranging from 0.5 to 20 weightpercent based on the total weight of said composition.
 8. Thecomposition of claim 7 wherein said thickening agent is a cellulosederivative.
 9. The composition of claim 3 which also contains one ormore of an antioxidant, a preservative, a perfume, a colorant or anotheranti-acne agent.